Compositions for the treatment of peripheral ulcers of various origins

ABSTRACT

The present invention relates to combinations of an agent that stimulates cell proliferation and an anti-inflammatory/analgesic, which are useful in the treatment of peripheral ulcers of various origins, such as radiation dermatitis, diabetic ulcers, ulcers caused by venous stasis of the limbs, bedsores, and the associated skin infections, proctitis, vulvovaginitis and haemorrhoids with vascular lesions. These combinations can be presented as formulations for topical use.

This U.S. non-provisional application is a divisional of U.S.application Ser. No. 14/935,036 filed on Nov. 6, 2015, which is acontinuation of U.S. application Ser. No. 14/342,618 filed on Mar. 20,2014, now U.S. Pat. No. 9,278,084, which is a U.S. National Stage ofPCT/EP2012/067893 filed on Sep. 13, 2012, which claims priority to andthe benefit of Italian Application No. MI2011A001671 filed on Sep. 16,2011, the contents of which are all incorporated by reference in theirentireties.

The present invention relates to bisulphite adducts of pureanthocyanosides or extracts containing them for use as topicalmedicaments in the treatment of ulcers and wounds.

The invention also relates to compositions containing said bisulphiteadducts as cell-proliferation-stimulating agents in association withanti-inflammatories/analgesics. The compositions according to theinvention are useful in the treatment of radiation dermatitis, burns,peripheral ulcers of various origins, such as diabetic ulcers, ulcerscaused by venous stasis of the limbs, bedsores, and the associated skininfections.

More particularly, the invention relates to compositions containingbisulphite adducts of pure anthocyanosides or extracts containing them,and extracts of Echinacea sp. The compositions can optionally alsocontain other active ingredients, such as natural or syntheticvasokinetics.

TECHNICAL BACKGROUND

Peripheral ulcers, whether they are of traumatic or metabolic origin,such as diabetic ulcers or those caused by venous stasis of the limbs,bedsores and the associated skin infections, have different etiologies,although they have some symptoms in common. Some involve the peripheralmicrocirculation and circulation, and are mainly connected witharteriosclerosis, which causes occlusion of the medium and smallarteries with consequent oedema which, due to accidental causes orscratching as a result of itching, can lead to a lesion that is slow toheal due to subsequent bacterial and/or fungal infection. Other ulcers,such as those caused by radiation or thermal or mechanical damage, andbedsores, have a definite origin.

Ulcers associated with chronic venous insufficiency require long-termtreatment with combinations of substances which have different, synergicactions. Diabetic ulcers have similar origins to the former, and areaccompanied by peripheral pain and purpura. Ulcers of traumatic originhave a strong antalgic component.

Vasokinetics and vasoprotectors in general improve wound healing,especially in the case of bedsores, although they alone are unable toheal the wound. The need is therefore felt for pharmacologicaltreatments that combine a wound-healing and vasokinetic action with ananalgesic and antiseptic/antibacterial action.

Keeping the arterial microcirculation active and removing proteinseepage from the ulcerated area by means of lymph drainage furtheraccelerates tissue re-epithelialisation.

DESCRIPTION OF THE INVENTION

It has been found that bisulphite adducts of anthocyanosides in pureform or extracts containing them possess better biological activity thanthe initial anthocyanoside.

It has also been found that the combination of said bisulphite adductsof anthocyanosides with lipophilic extracts of Echinacea sp inducessurprisingly rapid wound-healing, with a reduction in the surroundingoedema and re-epithelialisation, due to the immediate reduction infibrin production and protein seepage, which allows cleansing of thesore and rapid proliferation of granulation tissue.

The present invention therefore relates to compositions containing, asactive ingredients:

-   -   a) bisulphite adducts of anthocyanosides in pure form or of        extracts containing them,    -   b) lipophilic extract of Echinacea sp, and optionally    -   c) substances with a vasokinetic action.

The compositions according to the invention are useful in the treatmentof peripheral ulcers of various origins, such as radiation dermatitis,burns, haemorrhoids, stasis or diabetic ulcers, bedsores, and theassociated skin infections.

Substances with an anthocyanin backbone are well-known to possess invitro activity on fibroblast proliferation, antiprotease activity on theground substance of connective tissue, and vasokinetic activity atvenous and lymphatic level. However, these compounds are unsuitable fortopical administration because they cause undesirable, unacceptablestaining of the ulcers and the proximal tissue. Sulphur dioxide andbisulphite are known to interact with the bases of oxonium to give acolourless compound generating the following adducts:

where R is hydrogen or methyl.

The use of said adducts in pharmaceutical formulations explains theirconsiderable antibacterial and antifungal activity, which allows theelimination of antimicrobial stabilisers. The bisulphite adducts arebalanced with the anthocyanin compounds, but do not stain the tissuewith which they come into contact.

According to the present invention, said adducts can be formed directlyin the formulation by mixing anthocyanins/anthocyanosides with sulphitessuch as sodium metabisulphite. The adducts can be present in isolatedform, or in the form of extracts containing them. When present in theform of extracts, the following will preferably be used: Ericaceaeextracts, preferably from Vaccinium sp, such as Vaccinium myrtillus,Vaccinium erythrocarpon, Vaccinium macrocarpon, Vaccinium microcarpumand Vaccinium oxycoccos, Saxifragaceae extracts, preferably Ribesnigrum, Vitaceae extracts, preferably Vitis vinifera, Caprifoliaceaeextracts, preferably Sambucus nigra, and Elaeocarpaceae extracts,preferably Aristotelia chilensis.

Extracts of the ripe fruit of Vaccinium myrtillus, Vitis vinifera, Ribesnigrum or Sambucus nigra are preferred.

The term anthocyanosides comprises both anthocyanosides properly socalled and their aglycons (anthocyanidins).

According to a preferred aspect, the anthocyanosides preferably derivefrom bilberry (Vaccinium myrtillus) extracts. Bilberry extracts areknown to have a marked wound-healing activity, with the result that theyhave been used in the treatment of gastric and duodenal ulcers, and amarked anti-inflammatory action, especially at topical level, due totheir activity on capillary permeability and fragility. Bilberryanthocyanosides also have a bacteriostatic and antiviral action.

The preparation of bilberry extracts containing anthocyanosides isknown.

The lipophilic extract of Echinacea exercises an analgesic, antiviraland anti-inflammatory activity which produces a global improvement inwound-healing; it also has a significant effect on all forms of itching,a condition that often accompanies the formation of sores caused byvenostasis, and is useful in the healing, and above all prevention, ofsores. The analgesic effect due to the isobutylamide component isassociated with its interaction with cannabinoid receptors CB1 and CB2and activation of the vanilloids.

According to a preferred aspect of the invention, the lipophilic extractof Echinacea sp. is a lipophilic extract of Echinacea angustifolia orpurpurea.

The percentages of active ingredients can range from 0.05 to 2% forcatechin polyphenols or anthocyanosides, or extracts containing them,and from 0.01 to 1% for lipophilic extract of Echinacea sp.

A vasokinetic agent selected from visnadine or esculoside is preferablyadded for the treatment of bedsores.

The compositions according to the invention will preferably contain theactive components in the following percentage intervals:

-   -   a) bisulphite adducts of anthocyanosides or extracts containing        them: 0.05 to 2%, preferably 0.5 to 1%;    -   b) lipophilic extract of Echinacea sp.: 0.01 to 1%, preferably        0.05 to 0.3%;    -   and optionally    -   c) visnadine or esculoside from 0.2 to 1%, preferably visnadine        in the percentage of 0.5%.

The bisulphite adducts are formed by adding to the anthocyanins orextracts containing them a bisulphite in the quantity of approximatelyhalf the weight of the anthocyanoside or of an anthocyanin extracthaving an anthocyanoside content of 36±5%.

The compositions according to the invention can be administeredtopically, for example as water/oil emulsions, aseptic dusting powdersor occlusive formulations. According to a preferred aspect, theocclusive formulations will be in solid form, designed to be hydrated atthe time of application, and will contain alginic acid as gellingpolysaccharide.

The preferred excipients for use in the formulations arepolysaccharides, such as hyaluronic acid, chondroitin sulphate oralginic acid, which help to form a protective film that stimulates woundhealing.

The formulations are applied to the wound, and the formulation is leftto absorb. Particularly infected wounds should be covered with asticking plaster. The treatment is repeated one to three times a day,taking care to protect the wound or sore against mechanical traumas.

The compositions according to the invention will be prepared accordingto well-known conventional methods, such as those described in“Remington's Pharmaceutical Handbook”, Mack Publishing Co., N.Y., USA,together with suitable excipients.

The following examples illustrate the invention in detail.

EXAMPLE 1 Aqueous Gel

Vaccinium myrtillus (36% anthocyanosides) 0.50 g Echinacea angustifolia(root extract) 0.25 g Polyethylene glycol 400 5.00 g Glycerin 5.00 gCarbomer 1.00 g Sodium hydroxide 10% solution 2.00 g Sodium bisulphite0.20 g Propylparaben 0.05 g Potassium sorbate 0.15 g Purified water q.s.for  100 g

EXAMPLE 2 Cream (O/W Emulsion)

Vaccinium myrtillus dried extract 1.00 g Echinacea angustifolia (rootextract) 0.25 g Liquid paraffin 8.000 g Stearic acid 10.000 g Sodiumsulphite 0.5 g Polysorbate 80 2.000 g Glycerin 12.000 g Purified waterq.s. for 100.000 g

EXAMPLE 3 Effect on Ulcers Caused by Venous Stasis of the Lower Limbs

50 patients (10 in each group) suffering from ulcers of the lower limbscaused by venous stasis, not complicated by other vascular disorders,were included in the study.

The patients were treated with the preparation described in example 1,applied to the lesion in amounts of 2 cm (corresponding to 1 g) twice aday. The treated lesions were then covered with a bandage to ensure thatthe gel was not removed, and to protect them against external agentsand/or mechanical traumas. The lesions were monitored for 21 days, andre-epithelialisation was assessed by measuring the two diameters.

Results expressed as the mean of the two diameters measured

The results are set out in the table below.

RE-EPITHELIALISATION TREATMENT 7 days 14 days 28 days Placebo 0.02 ±0.01 0.01 ± 0.01 0.03 ± 0.02 Preparation example 1 2.14 ± 0.73**  4.9 ±1.01** 8.30 ± 1.10** Placebo + Vaccinium 0.10 ± 0.03 0.23 ± 0.13* 0.50 ±0.23* myrtillus 0.3% Placebo + Echinacea 0.01 ± 0.01 0.20 ± 0.02* 0.35 ±0.02* angustifolia 0.3% *P < 0.05; **p < 0.001 Student's “t” test

In the treatment of radiation dermatitis, the repair time of the damagecaused by the radiation in situ is evaluated: the most frequent types ofradiation dermatitis are those which occur in the treatment of head,neck, breast, uterus and prostate tumours. In these last cases,radiation treatment causes ulcers over large areas, and the treatmentcycle must be discontinued if rapid re-epithelialisation is impossible.

For example, in the case of tumours of the salivary glands, completeremission of the primary lesion in the external cervico-facial zone tookplace in 48 hours, competed with at least a week in normal oncologicalpractice.

It was also surprisingly found that the formulations according to theinvention reduce the regression time of proctitis induced byradiotherapy by 500% compared with untreated controls and patients givenconventional treatment.

1. A composition comprising: a) bisulphite adducts of anthocyanosidesfrom Vaccinium myrtillus, b) a lipophilic extract of Echinacea sp.. 2.The composition according to claim 1, wherein the lipophilic extract ofEchinacea sp. is a lipophilic extract of Echinacea angustifolia orEchinacea purpurea.
 3. The composition according to claim 1 containing0.05 to 2% of said bisulphite adducts and 0.01 to 1% of said lipophilicextract of Echinacea sp.
 4. The composition according to claim 1suitable for topical administration.
 5. A composition comprising a)bisulphite adducts of anthocyanosides from Vaccinium myrtillus, b)anthocyanosides from Vaccinium myrtillus; and c) a lipophilic extract ofEchinacea sp.
 6. The composition according to claim 5, wherein theextract of Echinacea sp. is a lipophilic extract of Echinaceaangustifolia or Echinacea purpurea.
 7. The composition according toclaim 5 containing 0.05 to 2% of said bisulphite adducts and 0.01 to 1%of said lipophilic extract of Echinacea sp.
 8. The composition accordingto claim 5 suitable for topical administration.